CD47, also known as integrin-associated protein (IAP), ovarian cancer antigen OA3, Rh-related antigen and MER6, is a widely expressed transmembrane receptor belonging to the immunoglobulin superfamily. CD47 is the counter-receptor for two members of the signal-regulatory protein (SHPS/SIRP) family and a high-affinity receptor for the secreted protein thrombospondin-1. Interactions with SIRP receptors play roles in self recognition and regulation of innate immune responses. Over-expression of CD47 on some cancers is a negative prognostic factor and protects against innate immune surveillance. Engagement of CD47 on vascular cells by thrombospondin-1 regulates calcium, cAMP, and nitric oxide/cGMP signaling pathways that control blood pressure, tissue perfusion, and angiogenesis. Moreover, CD47 signaling in various cell types regulates pathways that can trigger cell death, limit stem cell self-renewal, regulate mitochondrial homeostasis and other differentiation pathways, and activate protective autophagy responses under tissue stress. On red blood cells CD47 is part of the Rh complex, but on other cell types it associates laterally in the membrane with integrins and specific signaling receptors. Impaired responses to cardiovascular stress and some pathogens in mice lacking CD47 and their enhanced survival of fixed ischemia, ischemia/reperfusion and radiation injuries identify important pathophysiological roles for CD47 in inflammatory responses and adaptation to stress.